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Drug-Resistant Tuberculosis
Published in Lloyd N. Friedman, Martin Dedicoat, Peter D. O. Davies, Clinical Tuberculosis, 2020
Keertan Dheda, Aliasgar Esmail, Anzaan Dippenaar, Robin Warren, Jennifer Furin, Christoph Lange
Aminoglycosides, specifically amikacin and kanamycin, are FDA class D agents. These should be excluded from TB treatment regimens during pregnancy because of the risk of ototoxicity and fetal malformation, especially within the first 20 weeks of gestation. Bedaquiline may be used instead of SLID as it is likely safer (FDA pregnancy risk category B) and animal reproduction studies have not demonstrated risk to the fetus.210,211 Delamanid, however, should not be used in pregnancy until more safety data become available since animals studies have demonstrated potential teratogenic effects.212 Both bedaquiline and delamanid are excreted in breast milk in animal studies and therefore, the decision to discontinue the drug or nursing should be taken within the clinical context. Ethionamide is generally avoided as it can increase the risk of nausea and vomiting associated with pregnancy. This drug may be reintroduced after delivery if needed to strengthen the regimen in the immediate postpartum period.
Ethionamide and Prothionamide
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Ethionamide is active against M. tuberculosis, although resistance develops rapidly if used with ineffective companion drugs or when patients are incorrectly treated. Susceptibility is defined by the proportion method on Lowenstein-Jensen agar at a critical concentration of 30–40 µg/ml, on Middlebrook 7H10 agar at 2–3 µg/ml, and with the Bactec 460 system 1.0 µg/ml (Kam et al., 2010). In the Bactec MGIT 960 system, a critical concentration of 5 mg/ml has been recommended (Kim et al., 2013a; Lin et al., 2009; Rodrigues et al., 2008).
Clinical Pharmacology of the Anti-Tuberculosis Drugs
Published in Peter D O Davies, Stephen B Gordon, Geraint Davies, Clinical Tuberculosis, 2014
Abdullah Alsultan, Charles A. Peloquin
Ethionamide (ETA) is a singularly unpleasant drug to take because most patients will experience some GI intolerance [124]. In addition, it is perhaps the weakest of the TB drugs, so it is reserved for cases when there is nothing else [7,18,124].
Multidrug-resistant tuberculosis in children and adolescents: current strategies for prevention and treatment
Published in Expert Review of Respiratory Medicine, 2021
James A Seddon, Sarah Johnson, Megan Palmer, Marieke M van der Zalm, Elisa Lopez-Varela, Jennifer Hughes, H Simon Schaaf
Until recently, the WHO recommended a shorter regimen which consisted of an intensive phase of 4–6 months and a continuation phase of 5 months [37]. This regimen still included an injectable agent with high risk of irreversible hearing loss [40]. Therefore, some countries, such as South Africa, modified the shorter regimen by replacing amikacin with bedaquiline and moxifloxacin with levofloxacin. To protect bedaquiline against development of resistance while awaiting fluoroquinolone DST, linezolid was added for the first two months. Ethionamide was removed from the regimen due to being a relatively weak anti-TB drug, as well as being frequently associated with gastrointestinal intolerance. Following analysis of the outcomes seen in South African with this regimen, the use of bedaquiline in place of the injectables is now recommended by WHO [34]. This modified shorter regimen is currently only recommended in children >6 years of age, as bedaquiline dosing is uncertain in younger children.
Key considerations in the pharmacotherapy of tuberculous meningitis
Published in Expert Opinion on Pharmacotherapy, 2019
Sean Wasserman, Angharad Davis, Robert J. Wilkinson, Graeme Meintjes
Options for antitubercular therapy have been improved by registration of new compounds and introduction of repurposed drugs. Several agents, plus older drugs traditionally used in drug-resistant TB, fulfill the two key requirements for consideration in TBM therapy: enhanced activity against M. tuberculosis plus ability to achieve adequate CSF concentrations. Preliminary data suggest the novel nitroimidazole delamanid has a good brain and intralesional penetration in animal models [International Workshop on Clinical Pharmacology of Tuberculosis Drugs; Abstract 18. The Hague, October 2018] and may enter clinical studies for TBM in the future, as may potent new oxazolidinones currently under development. The older second-line agents, cycloserine (or terizidone, a condensation product containing two cycloserine molecules) and ethionamide have good CSF penetration [9] and have been used as substitutes for ethambutol in TBM; ethionamide-based regimens are associated with particularly good outcomes in pediatric TBM in South Africa [10]. However, the use of cycloserine and ethionamide is limited by dose-related neurological and gastrointestinal toxicity, respectively. Fluoroquinolones have undergone some evaluation with disappointing results. Linezolid has emerged as the most promising repurposed antimicrobial for TBM.
Intensified antibiotic treatment of tuberculosis meningitis
Published in Expert Review of Clinical Pharmacology, 2019
Fiona V. Cresswell, Lindsey Te Brake, Rachel Atherton, Rovina Ruslami, Kelly E. Dooley, Rob Aarnoutse, Reinout Van Crevel
Cycloserine and ethionamide achieve high concentrations in CSF, and the latter has been used successfully as a replacement for ethambutol to enhance TBM regimens in children [92,123,124]. Both can cause CNS adverse effects including psychiatric disturbances and there are dose-limiting gastrointestinal toxicities for ethionamide. Ethionamide can be changed for the chemically similar prothionamide, and cycloserine for terizidone (containing two molecules of cycloserine) can be used interchangeably in PTB, although there is limited evidence in TBM. Clofazimine does not penetrate CSF well but in a single mouse study showed widespread brain tissue distribution [125,126]. Studies in rats suggest that para-aminosalicylic acid can cross the BBB and BCSF barriers [127], in humans the CSF concentrations of PAS are low, even in the presence of meningitis [107].